Obesity is a condition in which the background of lack of exercise, intake of excessive energy, ageing, etc., leads to energy imbalance in the body. The surplus energy is accumulated generally as neutral fat (triacylglycerol, TG) in adipose tissue, and body weight and fat mass are thus increased. In recent years, the concept of metabolic syndrome associated with obesity involving the accumulation of visceral fat, as an upstream risk factor including a plurality of risk factors of diabetes, lipidosis, hypertension, etc. has been established, and the diagnostic criteria and therapeutic guidelines for metabolic syndrome were formulated (Journal of Japan Society for the Study of Obesity, vol. 12, Extra Edition, 2006). Since metabolic syndrome results in an increase in the risks of arteriosclerosis, cardiovascular disorder and cerebrovascular disorder, treatment of obesity has been recognized to be important for preventing these diseases.
Although the need for treating obesity is recognized to be important, there are extremely-limited drug therapies for obesity that are currently available, and there is no drug that is sufficiently satisfactory in terms of drug efficacy or side effects. Thus, development of novel antiobestic drugs having more definite action and few side-effects is desired.
Not less than 90% of lipid present in food is TG. TG derived from food is decomposed into 2-monoacylglycerol (2-MG) and free fatty acid (FFA) by the cleavage of the ester linkages of aliphatic acids at the 1- and 3-positions by lipase in digestive juice, which is secreted from the pancreas and the stomach. The 2-MG and FFA as well as bile acid are micellized and absorbed into small intestinal epithelial cells. The absorbed 2-MG and FFA resynthesize TG in the small intestinal cells, and the resynthesized TG as lipoprotein referred to as chylomicron (CM) is released into the lymph and supplied to the whole body. The TG resynthesis in the small intestinal cells is through two pathways, 2-MG and α-glycerophosphoric acid pathways. Typically, 80% of TG is resynthesized in the 2-MG pathway and the remaining 20% in the 2-plycerophosphoric acid pathways. The TG generated in the 2-MG pathway is utilized for generation of CM in accelerated turnover, and the synthesized CM is secreted into the intestinal lymph and then into blood and is transferred into peripheral tissue (Journal of Clinical Therapeutics and Medicine, vol. 21, No. 2, p. 216, 2005).
Enzymes such as MGATs (acyl-CoA:monoacylglycerol acyltransferases) and DGATs (acyl-CoA:diacylglycerol acyltransferases) are involved specifically in synthesis of TG in a 2-MG pathway. MGATs catalyze a reaction of generation of diacylglycerol by binding between 2-MG generated by lipase and fatty acyl-CoA, whereas DGATs catalyze a reaction of generation of TG by binding between the diacylglycerol generated by the catalytic reaction of the MGATs and fatty acyl-CoA.
Although such MGATs have been suggested to be present in the liver or white adipose tissue (J. Biol. Chem, vol. 259, p. 8934, 1984), the cloning of MGAT1 gene, a member of the family of MGATs, has been achieved in recent years, where the gene was isolated, as molecules expressed highly in the kidney, stomach, and white fat and brown fat cells, from a mouse (Proc. Natl. Acad. Sci. USA., vol. 99, p. 8512, 2002). However, although the activity of MGATs was observed significantly in the small intestine, no MGAT1 was expressed in the small intestine, and different molecules belonging to the family of MGATs were thus believed to be present.
Afterward, MGAT2 was cloned through homology search based on the cDNA sequence of MGAT1 by Cao et al., to isolate full-length cDNA from a cDNA library from the mouse small intestine (J. Biol. Chem, vol. 278, p. 13611, 2003). In addition, MGAT3 has been reported to be present in human (J. Biol. Chem, vol. 278, p. 13611, 2003), whereas no MGAT3 has been reported in rodents. The mouse MGAT2 is a 38.6-kDa protein including 334 amino acids, has an N-terminal 40-amino acid signal peptide, includes at least one transmembrane domain, and is expressed strongly in a small intestinal epithelial cell (J. Biol. Chem, vol. 278, p. 13860, 2003). In addition, both human and mouse MGATs2 were reported to include 334 amino acids and have 81% homology in human and mouse amino acid sequences, through the cloning of the human and mouse MGATs2, by Yen et al. (J. Biol. Chem, vol. 278, p. 18532, 2003). The expression pattern of MGAT2 in the small intestine has been exhibited to be similar to that of the site of absorbed lipid (J. Biol. Chem, vol. 279, p. 18878, 2004). In addition, the expression or activity of MGAT2 in the small intestine has been indicated to increase in high-fat diet-induced obesity mice (J. Biol. Chem, vol. 279, p. 18878, 2004) and OLETF rats exhibiting obesity or hypertriglyceridemia (Diabetes Res. Clin. Pract, vol. 57, p. 75, 2002), suggesting that MGAT2 is important for absorbing lipid and is involved in obesity or hypertriglyceridemia.
From the results, an MGAT2 inhibitor is expected to be useful as an agent for treating or preventing obesity, or type 2 diabetes, lipidosis, hypertension, fatty liver, arterial sclerosis, cerebrovascular disorder, coronary artery disease, etc., associated with obesity, through suppressing absorption of lipid.
As a compound having an MGAT2 inhibitory action, for example, a compound represented by the following structure:
has been disclosed (e.g., see WO 2008/038768). A compound according to an embodiment of the present invention is different from the compound disclosed in WO 2008/038768, in that the compound disclosed in WO 2008/038768 has substituted phenylaminocarbonyl at the 6-position of the 3,4,5,6,7,8-hexahydro-4-oxopyrido[4,3-d]pyrimidine ring whereas the compound according to an embodiment of the present invention has substituted benzimidazolyl. Furthermore, in WO 2008/038768, the substituted phenylaminocarbonyl is not disclosed or suggested to be replaced with substituted benzimidazolyl.